Composite stent with polymeric covering and bioactive coating

ABSTRACT

A composite expandable stent for delivery into a vessel carrying blood comprising an expandable support frame having first and second end portions. A porous imprevious polymer sleeve having inner and outer surfaces extending over the support frame. A coating is disposed on at least one of the inner and outer surfaces of the polymer sleeve for enhancing endothelial cell growth on the device and polymer sleeve. The stent can be cylindrical or tapered.

FIELD OF THE INVENTION

This invention relates to a composite expandable device with a polymericcovering on the device and a bioactive coating on device and thepolymeric covering, a delivery apparatus and a method.

BACKGROUND OF THE INVENTION

Saphenous vein grafts have heretofore been utilized for bypassingoccluded arterial blood vessels in the heart. Because they are veintissue rather than arterial tissue, they have different characteristicsand generally do not function well long term as arterial vessels.Saphenous bypass veins are less muscular and are generally quite flimsyand compliant. When these saphenous vein grafts become diseased withage, stenoses and obstructive deposits which are cheesy or buttery inconsistency and which are very malleable are formed which cannot betreated effectively with interventional catheter procedures even whenfollowed with a stent implant. The plaque material forming the stenosistends to ooze through the stent and reoccludes flow passage through thestent and the saphenous vein graft. Other vascular obstructions, such asin femoral and popliteal vessels and in carotids as well as in nativecoronary arteries also suffer from occlusions. In many of these cases,plaque proliferates through the stents when stents are deployed in thevessels. Therefore a great need exists for a new and improved device andmethod to provide a lasting therapeutic relief in such situations.

SUMMARY OF THE INVENTION

In general, it is an object of the present invention to provide acomposite expandable device with a substantially impervious polymericcovering thereon with a bioactive coating on the device and covering anda method for using the same which can be utilized for treatingocclusions or partial occlusions in blood vessels and particularlysaphenous vein grafts. In one embodiment, the polymeric covering isimpervious. In another embodiment, the polymeric covering is porous.

Another object of the invention is to provide a device of the abovecharacter which will provide a lasting therapeutic solution to theoccurrence of plaque in stents in saphenous vein grafts.

Another object of the invention is to provide a device of the abovecharacter which can be used for repaving with endothelial cells theportion of the vessel being treated. In one embodiment, the coating is acell adhesion peptide. In a related embodiment, the coating has theamino acid sequence presented as SEQ ID NO: 1.

Another object of the invention is to provide a device of the abovecharacter which has the physical characteristics which substantiallymatch or mimic the physical characteristics of blood vessels.

Another object of the invention is to provide a device of the abovecharacter in which a uniformly distributed structural support isprovided for the polymeric covering.

Another object of the invention is to provide a device of the abovecharacter which is very flexible and can bend axially to accommodate thetortuosity of blood vessels.

Another object of the invention is to provide a device of the abovecharacter which can be placed in tandem with another similar device in avessel to treat a long stenosis in a vessel.

Another object of the invention is to provide a device for delivery intoa vessel carrying a blood comprising a polymer sleeve having inner andouter surfaces, and a coating disposed on and attached to at least oneof the inner and outer surfaces of the polymer sleeve for enhancingendothelial cell growth on the polymer sleeve.

Additional objects and features of the invention will appear from thefollowing description in which the preferred embodiments are set forthin detail in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a side elevational view of a composite expandable device witha polymeric covering and a bioactive coating thereon, with certainportions broken away, mounted on a balloon delivery catheter.

FIG. 2 is a cross-sectional view taken along the line 2-2 of FIG. 1.

FIG. 3 is a cross-sectional view taken along the line 3-3 of FIG. 1.

FIG. 4 is an enlarged detailed view of the balloon with the compositeexpandable device mounted thereon shown in FIG. 1.

FIG. 5 is a plan view of the expandable device which has been splitapart longitudinally and spread out to show its construction.

FIG. 6 is a side elevational view of another embodiment of a compositeexpandable device with polymeric covering and bioactive coating thereonwhich is tapered and is carried by a tapered balloon for expansion anddelivery.

FIG. 7 is a schematic illustration of a heart showing the manner inwhich a saphenous vein graft is treated utilizing the compositeexpandable device of the present invention.

FIG. 8 is an enlarged detailed view showing the docking of a taperedcomposite expandable device being docked with a cylindrical compositeexpandable device.

FIG. 9 is a flow chart of one embodiment of the present invention.

FIG. 10 is a cross-sectional view of a medical device having a surfacetreated in accordance with one embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

In general, the composite expandable device incorporating the presentinvention is for delivery into a vessel carrying blood and comprises anexpandable support frame having first and second ends. An impervious orporous polymer sleeve extends over the support frame and may leave thefirst and second ends of the support frame exposed. A bioactive coatingis provided on one or both of the inner and outer surfaces of thepolymer sleeve and the frame for enhancing endothelial cell growth onthe blood contact surfaces of the polymer sleeve and frame.

More in particular, the composite expandable device 11 as shown ismounted on a delivery apparatus 12 which consists of an expandableballoon 13 mounted on the distal extremity of a shaft or catheter 14 andhaving a wye fitting 16 mounted on the proximal extremity. The shaft orcatheter 14 is provided with a central lumen 17 which is adapted toreceive a conventional guide wire 18 through a port 19 provided in thefitting 16. The catheter shaft 14 is provided with a concentric lumen 21which is in communication with a port 22 of the fitting 16. The lumen 21extends through the balloon 13 and an opening (not shown) is provided inthe shaft 14 within the balloon for inflating and deflating the balloon.

The composite expandable device 11 consists of an expandable frame 26which has a polymeric sleeve 27 covering the same. The sleeve has folds28 therein when the frame is in an unexpanded condition as shown in FIG.4.

The expandable balloon 13 has a substantially continuous diameter and isprovided with distal and proximal portions 31 and 32 and an intermediateportion 33 which serves as a working portion of the balloon, having alength which will accept the length of the composite device 11. Theballoon 13 is provided with folds 34 when deflated as shown in FIGS. 1,3 and 4. Radiopaque marker bands 36 and 37 are provided on the portionof the shaft 14 extending through the balloon 13 and are mounted in thedistal and proximal portions 31 and 32 as shown adjacent to theintermediate portion 33. These marker bands 36 and 37 are within thedistal and proximal portions 31 and 32 of the balloon 13 but have adiameter of the intermediate portion 33 with the composite expandabledevice 11 mounted on the intermediate portion 33 to serve as stops orabutments to prevent the composite expandable device 11 frominadvertently slipping off of the balloon 13 during positioning anddeployment of the composite expandable device 11.

The frame 26 which forms a part of the composite expandable device 11consists of a plurality of circumferentially spaced-apart elongatedstruts 41 having first and second ends 42 and 43. Foldable links 46 aresecured to the first and second ends 42 and 43 and extendcircumferentially of the frame 26 and serve in conjunction with theelongate struts to form a circular belt 47. As shown in FIG. 4, aplurality of serially-connected belts 47 are provided which are axiallyaligned with each other.

Sinusoidal-shaped end portions 48 and 49 are provided on opposite endsof the plurality of serially-connected belts 47. Interconnecting means50 is provided for interconnecting the plurality of belts 47 and the endportions 48 and 49 so that the belts 47 and end portions 48 and 49extend along an axis while permitting axial bending between the belts 47and the end portions 48 and 49 while maintaining a constant length ofthe device 11. The means 50 consists of at least one strut 51 which isrelatively short in length in comparison to the length of the elongatestruts 41 and a plurality of S-shaped links 52. Thus, as shown in FIGS.3 and 4, between each end portion and a belt and between adjacent beltsthere is provided a single strut 51 and two S-shaped links 52 all ofwhich are spaced 120° apart the interconnecting means between adjacentbelts and/or end portions are offset by 60°. Thus, with the constructionshown in FIG. 4 there are provided four belts 47 and two end portions 48and 49 with five sets of interconnecting means 50.

It can be seen that the length of the frame 26 can be readily increasedor decreased by changing the number of belts 47 provided in the frame26.

The frame 26 can be formed of a suitable material such as a metal orplastic. Suitable metals are stainless steel, titanium, and alloysthereof and other biocompatible metals. The plastic can be a polymer.Since the frame to be utilized in the composite expandable device istypically used in a saphenous vein graft, it need not have the radialstrength normally required for stents placed in native arterial vessels.The frame 26 has been specifically designed to support the polymersleeve 27 for use in saphenous vein graft to closely approximatemechanical properties of the saphenous vein graft. The same principlescan be used for a composite device for arterial vessels and other bloodvessels. Thus the frame 26 provides the necessary strength andconsistency throughout its length while giving good flexibilitythroughout its length to accommodate movement of the saphenous veingraft.

As shown in FIG. 3, the polymer sleeve extends over substantially theentire length of the frame 26 but leaving end portions 48 and 49substantially exposed for a purpose hereinafter described. The sleeve 27typically is formed of a suitable polymer. One polymer found to beparticularly satisfactory is PTFE which is supplied as a tube having awall thickness ranging from 0.002″ to 0.010″ and preferably 0.003″ to0.008″ and having a suitable original diameter as for example 2 to 4.5mm. The expanded PTFE material should have a pore size, or internodaldistance, of approximately 10 to 90 μm. Preferably the pore size orinternodal distance is between about 40 to 70 μm. In addition in certainapplications of this device, it may be desirable that the material beexpandable from two to six times its original size yet retain elasticityproperties to remain tightly over and in close engagement with the frame26 prior to and after expansion. After placing the sleeve 27 over theworking or intermediate portion 33 of the balloon, the sleeve 27 may besecured to the frame 26 during deployment as hereinafter described. Toaccomplish this, the sleeve 27 can be wrapped into a fold or a wing 28and held in place along a line 61 (see FIG. 4) or tacked by spaced-apartheat seals (not shown) that are easily rupturable upon expansion of theframe 26. It has been found that such tacking by the use of heat sealson a fold or wing of the polymer sleeve 27 makes it easy for the balloon13 when expanding to open the sleeve 27 without any significantadditional balloon pressure being required.

With such a construction as shown in FIG. 3, the frame 26 which has beencrimped onto the intermediate portion 33 of the balloon 13 and thesleeve 27 wrapped over onto the same and seamed into place will have anoverall profile which has a diameter or size which is not greater thanor desirably less than the diameters of the proximal and distal portions31 and 32. Since the marker bands 36 and 37 have larger diameters thanthe intermediate portion 33 of the balloon 13, they will ensure that thecomposite expandable device consisting of the frame 26 and the sleeve 27cannot inadvertently slip off of the balloon 13 during the procedure.

Another embodiment of a composite expandable device incorporating theinvention is in the device 71 shown in FIG. 5. It is tapered rather thancylindrical to more closely approximate natural vessel geometry. In thisdevice 71, a frame 72 is provided which is constructed in substantiallythe same manner as frame 26 but with the belts 73 increasingsuccessively in circumference in one direction along the axis of thedevice 71 by providing foldable links 46 of successively greater lengthsto provide the tapered construction shown in which one expandable endportion 76 has a lesser diameter than the other end portion 77. Themeans connecting the belts 73 and the end portions 76 and 77 are likethe interconnecting means 50 hereinbefore described.

A tapered polymer sleeve 81 is provided on the exterior of the frame 72while leaving the end portions 76 and 77 substantially exposed. Atapered balloon 86 is disposed within the frame 72 and is utilized forexpanding the composite expandable device 71. The tapered balloon 86 ismounted on the distal extremity of a balloon shaft or catheter 87 and isconstructed in the same manner as balloon shaft 14 and provides adelivery apparatus 89.

In order to provide a cell-friendly surface or surfaces on the sleeves27 and 81, at least one surface of the outer and inner surfaces andpreferably both inner and outer surfaces are treated in the followingmanner.

In general the method for treating a medical device having at least onesurface exposed to tissue and/or blood and comprises the steps ofsubjecting the one surface to a low temperature plasma of an appropriatechemical agent to provide a plasma deposited layer having functionalgroups like amine, carboxylic, or hydroxyl groups covalently bound tothe surface of the device. The plasma deposited layer is then subjectedto a chemical treatment with multifunctional linkers/spacers which thenbecome covalently bound with the plasma deposit layer. A bioactivecoating is then covalently bound to spacers/linkers.

More in particular, the method as hereinafter described utilizes aplasma chamber (not shown) of the type as described in U.S. Pat. No.5,643,580 well known to those skilled in the art and thus will not bedescribed in detail. Typically the plasma utilized in the method of thepresent invention utilizes a low temperature or cold plasma produced byglow discharge. A low temperature plasma is created in an evacuatedchamber refilled with a low pressure gas having a pressure on the orderof 0.05 to 5 Torr and with the gas being excited by electrical energyusually in the radio frequency range. A glow discharge is createdtypically in the range of 2-300 watts for low power and 50-1000 wattsfor high power depending on the chamber volume.

The steps for the method are shown in FIG. 9 for the treatment of asubstrate 111 shown in FIG. 10 and having first and second surfaces 112and 113. The substrate 111 is part of a medical implant or medicaldevice that has at least one surface which is to be treated, such as oneof the surfaces 112 and 113, to achieve desirable biological activitieson that surface. The substrate 111 is formed of a suitable material suchas a fluorinated thermoplastic or elastomer or more specifically, by wayof example, PTFE. The latter material is particularly desirable wherethe medical implant or medical device is in the form of small-diametervascular grafts. The substrate can also be formed of any polymer andpolymer composites, metals and metal-polymer composites.

Let it be assumed that the surface 112 of the substrate 111 is to betreated in accordance with the method set forth in FIG. 9. The surface112 is cleaned in an oxygen or air plasma as shown by step 116 in arelatively short period of time. The plasma cleaning process is anablation process in which radiofrequency power, as for example 50-1000watts, under a higher pressure e.g. 0.1 to 1.0 Torr at a high flow rate,as for example of at least 50 cc. per minute gas passing through theplasma chamber. Such a cleaning process can use oxygen, hydrogen alone,a mixture of oxygen with argon or nitrogen for a period of time of up to5 minutes. Thus, a plasma of oxygen, air, or inert gases can be utilizedfor plasma cleaning.

Thereafter, the surface 112 after being cleaned as shown in step 116, isfunctionalized as shown in step 117 by subjecting the surface 112 to apure gas or gas mixture plasma to assist in the deposition of functionalgroups on the surface 112 to provide a deposited layer 118 which iscovalently bound to the surface 112. Other methods which can be utilizedin place of the plasma deposition step 117 include a modification byirradiation with ultraviolet or laser light in the presence of organicamine or hydrazine. The plasma deposition step 117 used to achieveactivation of the surface utilizes precursor gases which can include thefollowing inorganic and organic compounds: NH₃ (ammonia), N₂H₄(hydrazine) aliphatic amines, aliphatic alcohols, aliphatic carboxylicacids, allylamine, water vapor, allyl alcohol, vinyl alcohols, acrylicacid, methacrylic acid, vinyl acetate, saturated or unsaturatedhydrocarbons and derivatives thereof. Precursors can be saturated(aliphatic amines, aliphatic alcohols, aliphatic acids) or unsaturated(allyl, vinyl and acrylated compounds). Employing unsaturated precursorsor operating pulsed plasma (single mode or gradient) tend to preservefunctional groups rather than form defragmentation products, having thepotential of introducing a significantly higher percentage of reactivegroups.

The deposition step 117 can be performed in continuous or pulsed plasmaprocesses. The power to generate plasma can be supplied in pulsed formor can be supplied in graduated or gradient manner, with higher powerbeing supplied initially, followed by the power being reduced or taperedtowards the end of the plasma deposition process. For example, higherpower or higher power on/off ratios can be utilized at the beginning ofthe step 117 to create more bonding sites on the surface 112 whichresults in stronger adherence between the substrate surface 112 and thedeposited layer 118. Power is then tapered off or reduced as for exampleby reducing the power-on period to obtain a high percentage offunctional groups on the surface 112.

The plasma deposition layer 118 created on the surface 112 has athickness ranging from 5-1000 Å. By way of example this can be a layerderived from allylamine plasma. This plasma-assisted depositiontypically is carried out at a lower power that ranges from 2-400 wattsand typically from 5-300 watts depending upon the plasma chamber size,pressure and gas flow rate. This step 117 can be carried out for aperiod of time ranging from 30 seconds to 30 minutes while being surethat the reactive group created is preserved.

When it is desired to retain only those functional groups in the layer118 which have established stable bonds to the substrate surface 112, asfor example to a PTFE surface, an optional step 121 can be performed byrinsing or washing off loosely bound deposits with solvents or buffers.Thus, deposits which are merely adsorbed on the surface 112 are rinsedand washed off and the covalently bound deposits remain on the surface.Such a step helps to ensure that parts of the coating forming the layer118 cannot thereafter be washed off by shear forces or ionic exchangeswith blood flow passing over the surface.

Plasma-assisted deposition has been chosen because it is a clean,solvent-free process which can activate the most inert substrates likePTFE. Plasma produces high energy species, i.e., ions or radicals, fromprecursor gas molecules. These high energy species activate the surface112 enabling stable bondings between the surface 112 and activatedprecursor gas. Allylamine has been chosen as a precursor for theplasma-assisted deposition step because it has a very low boiling pointof 53° C., making it easy to introduce as a gas into the plasma chamber.By using allylamine, the desire is to have radicals created by theplasma occurring preferentially at C═C double bonds so that the freeamine groups created are preserved for other reactions as hereinafterdescribed. Also, it is believed to give a high yield of the desiredprimary amine group on the surface 112.

In the rinsing step 121, a solvent rinse such as dimethylsulfoxide(DMSO) is used for removing all of the allyamine deposit which has notbeen covalently bound to the surface 112, i.e. to remove any allylaminewhich has only been adsorbed on the surface. Another material such asdimethylformamide (DMF), tetrahydrofuran (THF) or dioxane can beutilized as a solvent rinse. In addition, for removing polar deposits, abuffer rinse can be utilized. As soon as the rinsing step 121 has beencompleted and the substrate 111 dried, wetting or surface tensionmeasurement showed very hydrophilic PTFE (layer 118) completely wet withwater. The presence of free amine groups can be visualized by taggingfluorescent probes reactive with amine groups. ATR-FTIR (attenuatedtotal reflectance-fourier transform infrared) or ESCA (electronspectroscopy for chemical analysis) may give information about thepresence of amine or nitrogen in layer 118, respectively.

Subsequently, in step 123, homo or hetero multifunctionallinkers/spacers react and form stable linkages with the functionalgroups in layer 118 obtained by the plasma-assisted deposition process.This treatment in step 123 serves to provide linkers/spacers asrepresented by symbols 126 in FIG. 10 to improve accessibility ofcoating agents, as for example peptides and proteins, to functionalgroups on substrates. Vice versa, it is believed that the linkers 126enhance the exposure of peptides and proteins to the environment. Alsothe linkers give peptides or proteins in the final coating more spaceand freedom to assume their natural conformations. As a result, thecovalently bound coating agents are more likely to maintain theirnatural conformations and therefore their bioactivity.

By way of example, primary amine groups obtained after allylamine plasmareact with succinic anhydride leading to a substrate covered by linkers126 ended with COOH groups. Thus, the coverage with linkers 126 is lessthrombogenic and more cell-friendly compared to the coverage with NH₂rich layer 118. The linker/spacer attachment step 123 can also beutilized to introduce desirable functional groups which can readilyreact with the final coating agents. For example, COOH groups at the endof linker 126 can form stable amide linkage with NH₂ groups incell-adhesion peptides and proteins, anti-inflammatory peptides,anti-thrombogenic peptides and proteins, growth factors, etc. The COOHgroups can also form an ester linkage with OH groups in theanti-coagulant agent heparin. Taking the nature of the substrate,functional groups obtained after the plasma, the availability offunctional groups and the size and nature of the final coating agentsinto consideration, the chemistry and size of the linkers may beselected. Multifunctional linkers usually have 2-20 carbon atoms in thebackbone. They can be anhydrides of dicarboxylic acids, dicarboxylicacids, diamines, diols, or amino acids. Linkers can be just onemolecule, a string of several molecules, such as a string of aminoacids, a string of alternate dicarboxylic acids-diamines, dicarboxylicacids-diols or anhydrides-diamines. This chemical treatment step 123hereinbefore described can also be characterized as one that introducesother desirable functional or activating groups.

Organic solvents which are miscible with water can be used as solubilityenhancers to facilitate coupling efficiency between the plasma-treatedsubstrate and the linkers (step 123) and/or coating agents (step 128) inan aqueous medium. DMSO, DMF or dioxane can be used as such solubilityenhancers. They facilitate the contact between functional groups presentin molecules of different hydrophilicity or hydrophobicity. After thecorresponding functional groups present in molecules of differenthydrophilicity or hydrophobicity. After the corresponding functionalgroups come close enough to each other, chemical reactions between themcan occur. So, solubility enhancers in an aqueous solution can augmentthe binding reactions. The solubility enhancers may also enhance theaccessibility of the linker/coating agents to the functional groups onporous surfaces.

After completion of the wet chemistry linker/spacer attachment step 123,the wetting behavior/surface tension of the resulting surface can beanalyzed. Appropriate techniques, such as ESCA, SIMS, ATR-FTIR can beused to characterize the hydrophilic surface created in step 123.Fluorescent imaging of functional groups can also be carried out.

The bioactive/biocompatible coating step 128 can be carried out toprovide the final layer of coating 131 on the surface 112 of thesubstrate 111 (as shown in FIG. 10). In this step, the availablefunctional groups provided by the linkers 126, are used to covalentlybind molecules of a bioactive/biocompatible agent, such as acell-adhesion peptide P15 as hereinafter described, possessing desirableproperties to the substrate surface 112 to provide the final resultingcoating on the surface 112 as for example a PTFE surface. Of interestare bioactive/biocompatible coatings which, among others, can reduceforeign body reactions, accelerate the functioning and integration, aswell as increase the long-term patency of implants. Such coatings caninclude cell adhesion peptides, proteins or components of extra-cellularmatrix to promote cell migration and proliferation, leading to a rapidand complete coverage of the blood-contacting surface by a naturalendothelial cell lining. Coatings with growth factors such as VEGF maylead to similar results. Non-adhesive coatings with polyethylene glycolderivatives are used for biocompatible hydrophilic surfaces asseparation membranes, immuno barriers or surfaces free of plateletadhesion. Also, anti-thrombogenic coatings with hirudin, hirudinanalogs, reversible and irreversible thrombin inhibitor peptides, oranti-coagulant coatings with heparin are desirable to reduce or preventthrombosis formation at the implanting site. These localanti-thrombogenic or anti-coagulant coatings are more preferable than asystemic anti-coagulant treatment. Anti-inflammatory coatings can beused because occlusions may originate at inflamed sites.Anti-proliferative coatings are another way to reduce vessel occlusionsby preventing smooth muscle cell proliferation.

The covalent immobilization of bioactive/biocompatible agents ontosubstrate members according to the present invention is generallynon-reversible, i.e., the bioactive/biocompatible agent is not readilyreleased from the functional group or surface-modifying group. However,multi-functional groups capable of selectively releasing an immobilizedbioactive/biocompatible agent, including therapeutic drugs, have utilityin receptor/ligand interactions, molecular identification andcharacterization of antibody/antigen complexes, and selectivepurification of cell subpopulations, etc. In addition, a selectivelycleavable multifunctional linker affords predictable and controlledrelease of bioactive/biocompatible agents from the substrate.

Thus, the invention includes in one aspect a cleavable multi-functionallinker. In this embodiment, selective release of thebioactive/biocompatible agent is performed by cleaving the spacercompound under appropriate reaction conditions including, but notlimited to, photon irradiation, enzymatic degradation,oxidation/reduction, or hydrolysis, for example. The selective cleavageand release of immobilized agents may be accomplished using techniquesknown to those skilled in the art. See for example, Horton andSwaisgood, 1987; Wong, 1991; and U.S. Pat. No. 4,745,160, which isincorporated herein by reference. Suitable compounds for use ascleavable multifunctional linkers include, but are not limited to,polyhydroxyacids, polyanhydrides, polyamino acids, tartarates, andcysteine-linkers such as Lomant's Reagent.

Bioactive/biocompatible agents may be immobilized onto the substrateusing bioconjugation techniques known to those skilled in the art. SeeMosbach, 1987; Hermanson, et al., 1992; and Brinkley, 1992; for example.Mild bioconjugation schemes are preferred for immobilization ofbioactive/biocompatible agents in order to eliminate or minimize damageto the structure of the substrate, the functional groups, thesurface-modifying groups, and/or the bioactive/biocompatible agents.

Bioactive/biocompatible agents of the present invention are typicallythose that are intended to enhance or alter the function or performanceof a particular substrate or alter the reactions and functions of thesurrounding tissues. In one embodiment, biomedical devices for use inphysiological environments are substrates contemplated by the presentinvention. In a particularly preferred embodiment, thebioactive/biocompatible group is selected from the group consisting ofcell attachment factors, growth factors, antithrombotic factors, bindingreceptors, ligands, enzymes, antibiotics, and nucleic acids. The use ofone bioactive/biocompatible agent on a substrate is presently preferred.However, the use of two or more bioactive/biocompatible agents on asubstrate is also contemplated in one embodiment of the invention.

In a related embodiment, the invention includes a firstbioactive/biocompatible agent that may be released slowly, and a secondbioactive/biocompatible agent that may be released faster, e.g. byphysical desorption. This combination would have an advantage indifferent phases in the course of disease treatment, wound healing, orincorporation of an implantable device. An exemplary slow release agentis released by hydrolysis of an ester bond formed between an OH group onthe bioactive agent and the COOH formed on the substrate surface.

Desirable cell attachment factors include attachment peptides, as wellas active domains of large proteins or glycoproteins typically 100-1000kilodaltons in size, which in their native state can be firmly bound toa substrate or to an adjacent cell, bind to a specific cell surfacereceptor, and mechanically attach a cell to the substrate or to anadjacent cell. Attachment factors bind to specific cell surfacereceptors, and mechanically attach cells to the substrate or to adjacentcells. Such an event typically occurs within, well defined, activedomains of the attachment factors. Factors that attach cells to thesubstrate are also referred to as substrate adhesion molecules herein.Factors that attach cells to adjacent cells are referred to as cell-celladhesion molecules herein. In addition to promoting cell attachment,each type of attachment factor can promote other cell responses,including cell migration and differentiation. Suitable attachmentfactors for the present invention include substrate adhesion moleculessuch as the proteins laminin, fibronectin, collagens, vitronectin,tenascin, fibrinogen, thrombospondin, osteopontin, von WillibrandFactor, and bone sialoprotein, or active domains thereof. Other suitableattachment factors include cell-cell adhesion molecules, also referredto as cadherins, such as N-cadherin and P-cadherin.

Attachment factors useful in this invention typically comprise aminoacid sequences or functional analogues thereof that possess thebiological activity of a specific domain of a native attachment factor,with the attachment peptide typically being about 3 to about 20 aminoacids in length. Native cell attachment factors typically have one ormore domains that bind to cell surface receptors and produce the cellattachment, migration, and differentiation activities of the parentmolecules. These domains consist of specific amino acid sequences,several of which have been synthesized and reported to promote theattachment, spreading and/or proliferation of cells. These domains andfunctional analogues of these domains are termed attachment peptides.

Exemplary attachment peptides from fibronectin include, but are notlimited to, RGD or Arg Gly Asp (SEQ ID NO:2), REDV or Arg Glu Asp Val(SEQ ID NO:3), and C/H-V (WQPPRARI or Trp Gin Pro Pro Arg Ala Arg Ile)(SEQ ID NO:4).

Exemplary attachment peptides from laminin include, but are not limitedto, YIGSR or Tyr Ile Gly Ser Arg (SEQ ID NO:5) and SIKVAV or Ser Ile LysVal Ala Val (SEQ ID NO:6) and F-9 (RYVVLPRPVCFEKGMNYTVR or Arg Tyr ValLeu Pro Arg Pro Val Cys Phe Glu Lys Gly Met Asn Tyr Thr Val Arg) (SEQ IDNO:7).

Exemplary attachment peptides from collagen include, but are not limitedto, HEP-III (GEFYFDLRLKGDK or Gly Glu Phe Tyr Phe Asp Leu Arg Leu LysGly Asp Lys) (SEQ ID NO:8) and P15 (GTPGPQGIAGQRGW; SEQ ID NO:1)Desirably, attachment peptides used in this invention have between about3 and about 30 amino acid residues in their amino acid sequences.Preferably, attachment peptides have not more than about 15 amino acidresidues in their amino acid sequences. In one embodiment, attachmentpeptides have exactly 15 amino acid residues in the amino acidsequences.

An embodiment of the present invention involves synthetic compositionsthat have a biological activity functionally comparable to that of allor some portion of P15 (SEQ ID NO: 1). By “functionally comparable,” ismeant that the shape, size, and flexibility of a compound is such thatthe biological activity of the compound is similar to the P15 region, ora portion thereof. Biological activities of the peptide may be assessedby different tests including inhibition of collagen synthesis,inhibition of collagen binding, and inhibition of cell migration on acollagen gel in the presence of the peptide in solution. Of particularinterest to the present invention is the property of enhanced cellbinding. Useful compounds could be selected on the basis of similarspatial and electronic properties as compared to P15 or a portionthereof. These compounds typically will be small molecules of 50 orfewer amino acids or in the molecular weight range of up to about 2,500daltons, more typically up to about 1000 daltons. Inventive compounds ofthe invention include synthetic peptides; however, nonpeptides mimickingthe necessary conformation for recognition and docking of collagenbinding species are also contemplated as within the scope of thisinvention. For example, cyclic peptides on other compounds in which thenecessary conformation is stabilized by nonpeptides (e.g., thioesters)is one means of accomplishing the invention.

The central portion, forming a core sequence, of the P15 region has beenidentified as having collagen-like activity. Thus,bioactive/biocompatible agents of this Invention may contain thesequence Gly-Ile-Ala-Gly (SEQ ID NO: 9). The two glycine residuesflanking the fold, or hinge, formed by -Ile-Ala- are hydrogen bonded atphysiologic conditions and thus stabilize the [beta]-fold. Because thestabilizing hydrogen bond between glycines is easily hydrolyzed, twoadditional residues flanking this sequence can markedly improve the cellbinding activity by further stabilizing the bend conformation. Anexemplary bioactive/biocompatible agent with advantageous propertiescontemplated by the present invention, having glutamine at each end(Gln-Gly-Ile-Ala-Gly-Gln; SEQ ID NO: 10) is described in U.S. Pat. No.6,268,348, issued Jul. 31, 2001, which is incorporated by reference inits entirety herein.

Chemical/biological testing such as MA (amino acid analysis), in vitrocell cultures followed by SEM (scanning electron microscopy), and invivo testing can be used for evaluating the coatings of the presentinvention.

A specific example of a coating having biological activity and medicalimplants having a surface carrying the same and the method incorporatingthe present invention may now be described as follows.

Let it be assumed that it is desired to coat long porous PTFE tubes, asfor example having a length of 11 cm., which are to be utilized asmedical implants and to be treated with a coating using the method ofthe present invention. The tubes can be prepared for treatment bymounting the same on an anodized aluminum wire frame and then insertingthem in a vertical position in the upper portion of the plasma chamberbeing utilized. The tubes are then cleaned in an air plasma by operatingthe plasma chamber at 0.3 Torr at 50 watts for 3 minutes. After theplasma cleaning operation has been performed, the chamber is flushedwith allylamine gas at 0.2 Torr for 10 minutes. Allylamine plasma isthen created at 0.2 Torr at 15 watts for 30 minutes. Radiofrequencypower is turned off and allylamine is permitted to flow at 0.2 Torr for2 minutes. The allylamine flow after plasma treatment is provided toreact with any free radicals on the PTFE. The allylamine flow is thenterminated and a vacuum is maintained in the chamber for 15 minutes.Thereafter, the pressure in the plasma chamber is increased toatmospheric pressure. The tubes being treated are then removed from thechamber and transferred to clean glass rods. The tubes are thensubmerged and rinsed in an appropriate volume of DMSO. The samples arethen removed from the DMSO rinse and washed with deionized (DI) waterand optionally ultrasonically at room temperature for 3 minutes.

In the covalent linker attachment step 123, a 1 M (one molar) succinicanhydride solution is prepared using DMSO and placed in a covered glasstray container. The plasma treated and optionally rinsed tubes are thensubmerged in the succinic anhydride solution in the glass tray containerand subjected to an ultrasonic mix at 50° C. in order to bring thesuccinic anhydride into close proximity to the free amine groups on thePTFE surface. A one molar (1M) Na₂HPO₄ solution in DI water is used toadjust the pH between 6 to 9, preferentially pH 8. A higher pH resultsin a faster reaction. This reaction between the free amine groups andthe succinic anhydride can be carried out between room temperature and80° C. and preferentially between 20-50° C.

After this has been accomplished, the tubes are removed and rinsed withDI water optionally utilizing ultrasound. The tubes are then dried withnitrogen.

Let it be assumed that a peptide coating is desired to be applied to thesurface thus far created. Solubility enhancers such as DMSO and DMF canbe added between 0-50 volume/volume v/v %, preferentially 10-30%. A 90mL. DI water/DMSO solution is prepared by taking 70 mL. of DI water andmixing the same in a glass container with 20 mL. of DMSO. The driedtubes are then placed in the DMSO solution and ultrasonically mixed fora period of 1 minute.

Freshly prepared EDC [N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride] (Fluka) solution in 5 ml DI water is poured over thetubes submerged in water/DMSO to activate COOH groups on the PTFEsurface. After 0.5-3 min., P15((H-Gly-Thr-Pro-Gly-Pro-Gln-Gly-Ile-Ala-Gly-Gln-Arg-Gly-Val-Val-OH; SEQID NO: 1) acetate salt, GLP grade peptide) solution in 5 ml DI water isadded. For hydrophobic peptides, the peptides may be dissolved in anorganic solvent miscible with water (DMSO, DMF or dioxane). EDC and P15amounts are based on the following final concentrations: 0.02 M EDC tobe used and 0.0002 M P15 in the final reaction volume, i.e. 100×molarexcess of EDC to P15. The reaction at room temperature is carried outbetween 1-16 hours, preferentially 2-8 hours. The tubes are then rinsedseveral times with deionized water with an optional one minuteultrasonic treatment. The tubes are then dried with nitrogen gas. Thetubes are then inverted to bring the coated side to the inside. Aminoacid analysis revealed that up to 1.5 nmol P15/cm² was bound to the PTFEsurface.

From the foregoing it can be seen that there has been provided a coatingwhich has biological activities which can be utilized on surfaces ofmedical implants and devices and a method for accomplishing the same.The coating and method can be utilized on many different types ofdevices which are intended to be implanted in the human body or in otherwords to remain in the human body for a period of time. Such devicesinclude stents and grafts placed in various vessels of the human body.Other medical devices such as heart valves, defibrillators and the likehave surfaces which are candidates for the coating and method of thepresent invention. The coating and method is particularly advantageousfor use on surfaces which heretofore have been difficult to obtain cellgrowth on, as for example PTFE and ePTFE. By utilizing the coating andmethod of the present invention, it has been found that cell growth hasbeen greatly enhanced, making possible long term implantation of saiddevices in the human body.

Thus the surface of the polymer can be characterized as having appliedthereto a bioactive coating which is cell friendly and which enhancesgrowth of cells thereon. As described above, a low temperatureplasma-deposited layer is provided on the surface of the polymer tofunctionalize the surface and provide free amine groups thereon. Aspacer/linker molecular layer is covalently bonded to theplasma-deposited layer. A peptide coating such as P15 is deposited onthe spacer/linker layer. By way of example, the outer surface of thesleeve 27 can be treated first. Thereafter, the sleeve 27 can beinverted by turning it inside out and treating the inside surface whichis now outside. Alternatively, both the outside and inside surfaces canbe treated at the same time.

Operation and use of the composite expandable devices 11 and 71 with thedelivery apparatus 12 and delivery apparatus 89 may now be brieflydescribed as follows. In this connection let it be assumed that a humanheart 101 as shown in FIG. 6 has previously had a coronary artery 102 inwhich there had been formed therein a substantially total occlusion 103.Also let it be assumed that it was found necessary to perform a bypassoperation and to insert a saphenous vein graft utilizing a length ofsaphenous vein 106 which has one end connected into the aorta 107 of theheart by a proximal anastomosis 108 for a blood supply and bypassing thecoronary artery occlusion 103 and making a connection to the coronaryartery occlusion 103 and making a connection to the coronary artery 102at a distal anastomosis 109. Now let it be assumed that after a periodof time there has been a build-up of plaque forming a stenosis in thesaphenous vein graft 106 in the region near the distal anastomosis 109.

With such a condition, it is desirable to first use a tapered compositeexpandable device 71, delivering the same by the use of the taperedballoon 86 of the delivery apparatus 89 on a guide wire in aconventional manner through the femoral artery into the aorta, thenthrough the proximal anastomosis 108 and then advanced into a regionadjacent the distal anastomosis 109. The distal tapered balloon 86 isthen expanded to expand the device 71 into engagement with the wall ofthe saphenous vein graft and to thereby enlarge the opening through thesaphenous vein graft to enhance blood flow therethrough, through theflow passage formed by the device 71. Thereafter, the tapered balloon 86and the delivery apparatus 89 is removed.

Let it be assumed that the tapered device 71 has an inadequate length totreat the entire stenosis and it is desired to place another compositeexpandable device as for example the device 11 (FIG. 1) in tandem or inseries with the device 71. Assuming that the guide wire is in place thatwas used for deploying the first device 71, the shaft 14 of the deliveryapparatus 12 can be threaded over the guide wire 18 and a balloon with acomposite expandable device 11 mounted thereon advanced into thesaphenous vein graft 106 until the distal extremity of the device 11meets within the proximal larger end 77 of the device 71. The distalextremity can be docked into the open proximal end of the device 71.Thereafter, the balloon 13 can be expanded to complete the docking ofthe distal extremity of the device 11 in the proximal extremity of thedevice 71 so that they are deployed in the saphenous vein graft 106 intandem. The balloon 13 then can be deflated and removed with thedelivery apparatus 12 along with the guide wire 18. The positioning ofthe devices 71 and 11 can be observed fluoroscopically by observing thelocations of the radiopaque markers 56 provided on the devices 11 and71. If the occlusion in the saphenous vein graft is sufficiently long,an additional device 11 can be placed in tandem with the device 11already in place. If this is desired, the guide wire can be left inplace and another balloon delivery apparatus 12 with a device 11 mountedthereon can be advanced into the saphenous vein graft 106 and the distalextremity docked into the expanded proximal extremity of the alreadypositioned device 11. The balloon 13 can be deflated and then removedalong with the guide wire 18 and the femoral artery closed in anappropriate manner.

From the foregoing it can be seen that the balloon expandable devices 11and 71 form a vascular prosthesis which has mechanical and biomedicalproperties which re-establish and mimic the composition of thebiological function and environment of a healthy natural vessel as forexample a recently transplanted saphenous vein graft. The support framefor the polymer sleeve is designed to provide adequate support for thepolymer sleeve while still providing appropriate compliancecorresponding to that of the vessel in which it is disposed. The devicewith its free outer ends is capable of firmly engaging the wall of thevessel in which it is disposed to ensure that the device remains inplace in the desired position within the vessel after deployment. By theuse of the cylindrical and tapered devices, it is possible to constructa vascular prosthesis which corresponds to the natural geometry of thevessel. The delivery apparatus has a low profile which by utilizing aballoon having an intermediate working portion of a lesser diameterretains this low profile even when the composite expandable device ismounted thereon to facilitate positioning and deployment of the deviceto the site. Use of the polymer sleeve in the device prevents plaque ordeposits within the blood vessel as for example a saphenous vein graftfrom oozing through the interstices of the frame so that there isunimpeded blood flow through the expanded frame. By covering the polymersleeve with a peptide such as P15, endothelial cell growth isstimulated. In this way, it is possible to repave the vessel withendothelial cells, nature's most blood compatible surface, and helpprevent further spread or degradation of the lumen in the vessel at thatsite. The construction of the device permitting axial bending makes itpossible for the expanded device to readily flex with the vessel. TABLE1 Sequence Provided In Support Of The Invention. Description SEQ. ID NO.P15 1 GTPGPQGIAGQRGVV RGD 2 REDV 3 C/H-V 4 WQPPRARI YIGSR 5 SIKVAV 6 F-97 RYVVLPRPVCFEKGMNYTVR HEP-III 8 GEFYFDLRLKGDK Gly-Ile-Ala-Gly 9Gln-Gly-Ile-Ala-Gly-Gln 10

1. A composite expandable device for delivery into a vessel carrying ablood comprising an expandable support frame having first and second endportions, a polymer sleeve extending over the support frame and havinginner and outer surfaces, and a coating disposed on and attached to atleast one of the inner and outer surfaces of the polymer sleeve forenhancing endothelial cell growth on the polymer sleeve.
 2. A device asin claim 1 wherein said polymer sleeve is porous.
 3. A device as inclaim 1 wherein said polymer sleeve is impervious.
 4. A device as inclaim 1 wherein both the inner and outer surfaces are coated with thecoating.
 5. A device as in claim 1 wherein the first and second endportions are exposed and free of the sleeve.
 6. A device as in claim 1wherein said expandable support frame and polymer sleeve arecylindrical.
 7. A device as in claim 1 wherein said expandable supportframe and polymer sleeve are tapered.
 8. A device as in claim 1 whereinsaid expandable support frame is constructed to maintain its lengthduring expansion of the frame.
 9. A device as in claim 1, wherein saidcoating is prepared by treating said inner or outer surface with agaseous plasma cleaning process utilizing radiofrequency energy toablate said inner or outer surface and to functionalize said inner orouter surface and to produce a plasma-deposited layer having functionalgroups, and subjecting said plasma-deposited layer to multifunctionallinkers/spacers in a wet chemical tratement to form covalent bondsbetween the linkers/spacers adn the functional groups of theplasma-deptosited layer to covalently bind the cell-adhesion peptides tosaid inner or outer surface of the substrate.
 10. A device as in claim 1wherein said coating is a cell adhesion peptide.
 11. A device as inclaim 10 wherein said cell-adhesion peptide has the amino acid sequencepresented as SEQ ID NO:
 1. 12. A device as in claim 1 wherein saidexpandable support frame includes a plurality of axially aligned beltsand first and second end portions, each of said belts comprising aplurality of circumferentially spaced struts having first and secondends and foldable links secured to the first and second ends of thestruts and interconnecting means serially interconnecting the belts andthe first and second end portions to extend along an axis and permittingaxial bending between the belts and the end portions while maintainingthe length of the device.
 13. A device as in claim 12 wherein saidinterconnecting means includes at least one strut and a plurality ofS-shaped links.
 14. A device as in claim 12 wherein said interconnectingmeans includes a single strut and first and second S-shaped links, allspaced 120° apart.
 15. A device as in claim 12 wherein saidinterconnecting means between adjacent belts are offset angularly withrespect to each other.
 16. A device as in claim 15 wherein said endportions are sinusoidal.
 17. A device as in claim 12 further includingradiopaque markers carried by the end portions.
 18. A device as in claim1 wherein said sleeve is provided with a fold and further includingmeans for securing said label to said sleeve to inhibit dislodging ofthe sleeve from the frame during deployment of the device.
 19. Adelivery apparatus for an expandable device having a length and an innerdiameter comprising a shaft, a balloon mounted on the shaft, said shafthaving a lumen therein for inflating and deflating the balloon, saidballoon being formed with proximal, distal and intermediate portions,said intermediate portion having a length to receive the expandabledevice, and radiopaque markers carried within the proximal and distalportions of the balloon and sized so that they have a diameter greaterthan the inner diameter of the expandable device when it is mounted onthe intermediate portion of the balloon for securing the expandabledevice to the intermediate portion to prevent the expandable device frombeing dislodged during deployment by the delivery apparatus, theproximal and distal portions of the balloon being sized so that theyhave a size which is greater than the size of the expandable device whenplaced on the intermediate portion to inhibit inadvertent dislodgment ofthe expandable device during deployment of the expandable device withthe apparatus.
 20. A method for deploying a plurality of compositeexpandable devices comprising an expandable frame having opposite endsat proximal and distal extremities, a polymeric sleeve extending overthe frame, with the use of a balloon delivery catheter having aninflatable balloon on the distal extremity thereof comprising the stepsof mounting a first composite expandable device on the balloon,utilizing the balloon delivery catheter to deliver the device to thedesired site in the vessel, inflating the balloon to expand the devicein the vessel, deflating the balloon and removing the balloon from thevessel, utilizing a balloon delivery catheter to deliver a secondcomposite expandable device to the site and docking the distal extremityof the additional composite expandable device in the proximal extremityof the first composite device already in place by causing theextremities to intermesh with each other, expanding the balloon toexpand the second composite expandable device to expand the distalextremity within the proximal extremity of the composite expandabledevice already in place to complete the docking and deflating theballoon and removing the balloon delivery catheter from the vessel. 21.A method as in claim 20 wherein the first device is a tapered device.22. A device for delivery into a vessel carrying a blood comprising apolymer sleeve having inner and outer surfaces, and a coating disposedon and attached to at least one of the inner and outer surfaces of thepolymer sleeve for enhancing endothelial cell growth on the polymersleeve.